DESC:

FORM 2
THE PATENT ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See section 10; rule 13)

“A PROCESS FOR THE PREPARATION OF 1-(4-NITROPHENYL) PIPERIDIN-2-ONE”

Hikal Limited, an Indian Companyof 3A & 3B, International Biotech Park, Hinjewadi, Pune – 411 057, India

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of 1-(4-Nitrophenyl) piperidin-2-one.The present invention further relates to a process for the preparation of 1-(4-Nitrophenyl) piperidin-2-one by oxidation of 1-(4-Nitrophenyl) pieridineusing acid or acid salt.

BACKGROUND OF THE INVENTION
Apixaban is chemically known as 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide and was found potent as direct inhibitor of factor Xa. Apixaban is commercially available as Eliquis in pharmaceutical preparation. It is an anticoagulant useful for treatment of venous thromboembolic event also indicated the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Apixaban is developed by Bristol-Myers Squibb and Pfizer.

A 1-(4-Nitrophenyl) piperidin-2-one is a key intermediate for the synthesis of Apixaban, having the following structure:

Several methods for the preparation of 1-(4-Nitrophenyl) piperidin-2-onehas been described in the literature the few of them described herein.

The publication Synlett (2022), 33 (10), 993-997 disclosesthe processfor preparation of 1-(4-Nitrophenyl) piperidin-2-one by oxidizing of 1-(4-nitrophenyl) piperidine with aqueous sodium chlorite in acetonitrile under the catalyst carbon dioxide.

The Chinese Patent publication115215816 disclosesthe process for preparation of lactam compound that uses sodium chlorite as an oxidant under the catalyst carbon dioxide . This patent publication also disclosed specifically preparing 1-(4-Nitrophenyl) piperidin-2-one by reacting 1-(4-nitrophenyl) piperidine with aqueous sodium chlorite in butyronitrile as a solvent under the catalyst carbon dioxide.

The Indian patent publication4558/CHE/2012 discloses a process for preparing 1-(4-Nitrophenyl) piperidin-2-one by oxidizing1-(4-nitrophenyl)piperidine in presence of potassium permanganate andbenzyl triethyl ammonium chloride in dichloromethane.

Although several processes have been reported for the oxidation of 1-(4-Nitrophenyl) piperidine and preparation of 1-(4-Nitrophenyl) piperidin-2-one intermediate, they suffer from one or more drawbacks such as:i) use of carbon dioxide and high pressure equipment; ii)use of potassium permanganatewhich generates huge solid waste which further required huge amount for its disposal; iii) use of carcinogenic chlorinated solvent such a dichloromethane ;vii) more unit operations and long cycle time; thus, overall processes are not economic, and environmental friendly.

Therefore, there was a need to develop an economic and environment friendly process for preparation of 1-(4-Nitrophenyl) piperidin-2-one which involves commercially available oxidizing agent which result in good yield and quality product.

SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of 1-(4-Nitrophenyl) piperidin-2-one of formula (I)

comprising
i) dissolving1-(4-nitrophenyl)piperidine of formula (II)

in solvent;
ii) oxidizing 1-(4-nitrophenyl)piperidine of formula (II) using sodium chlorite in presence of acid or acid salt to obtain 1-(4-Nitrophenyl) piperidin-2-one.

DETAILED DESCRIPTION OF THE INVENTION
The present invention now will be described more fully hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements.

As used in the specification, the singular forms “a,” “an,” “the,” include plural referents unless the context clearly indicates otherwise.

The term solvent used herein refers to the single solvent or mixture of solvents.

The term dissolving as used herein refers to the process by which a solid substance is dispersed in a medium in a molecular form.

In accordance with the objectives, the present invention provides a process for the preparation of1-(4-Nitrophenyl) piperidin-2-one of formula (I).

The inventors of the present invention developed a process which does not require separate and/or multiple purification steps.

The present invention is more broadly elaborated in following embodiment.

In oneembodiment of the present invention, the preparation of 1-(4-Nitrophenyl) piperidin-2-one of formula (I) is characterized by dissolving 1-(4-nitrophenyl)piperidine of formula (II) in solvent followed by oxidizing using sodium chlorite in presence of acid or acid salt.

In the present invention the oxidizing agentis Sodium chlorite.

In another embodiment of the present invention, wherein solvent is aprotic solvent and is selected from acetone, acetonitrile, propionitrile, butyronitrile, dimethylformamide (DMF), dimelthylsulfoxide (DMSO), dimethylacetamide (DMAC), methanol, ethanol, toluene,and the like,more preferablyacetonitrile or acetone.

In another embodiment of the present invention, wherein the acid or acid salt is selected from formic acid, acetic acid, hydrochloric acid,phosphoric acid, carbonic acid, sodium dihydrogen phosphate, sodium hydrogen sulfate, and the like;more preferably acetic acid or sodium dihydrogen phosphate.

In another embodiment of the present invention,acid or acid salt is used to control the pH value of the reaction system to be less than 7.

In another embodiment of the present invention, the molar ratio of the compound of formula II to the oxidizing agent is 1:1 to 1:10, and the molar ratio of the oxidizing agent to the acid or acid salt is 1:0.1 to 1:5.

In another embodiment of the present invention, the reaction time is 0.5 to 24 hoursand temperature are0 to 100°C.

In another embodiment of the present invention, wherein after the completion of the reaction the 1-(4-Nitrophenyl) piperidin-2-one of formula (I) is extracted using aromatic solvent selected from Xylene, toluene,trimethylbenzene and the like;more preferably toluene.

In another embodiment of the present invention, wherein 1-(4-nitrophenyl)piperidine of formula (II) can be prepared by the methods known in the art.

In another embodiment of the present invention,the 1-(4-Nitrophenyl) piperidin-2-oneof formula (I)obtained has purity greater than 90%by HPLC.

In another embodiment of the present invention, wherein the 1-(4-Nitrophenyl) piperidin-2-one of formula (I) obtained is further converted into Apixaban by the methods known in the art.

The process of the present invention is illustrated in the following general synthetic scheme:

The following example(s) illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXPERIMENTAL:

Example 1: Preparation of1-(4-Nitrophenyl) piperidine (II).
A potassium carbonate (0.6981 mol) was added to the solution of piperidine(0.6981 mol) and 1-chloro-4 nitro benzene (0.6346 mol) in 500 mL in DMSO. The content was heated to 115-125 °C. After completion of reaction, the reaction mixture was cooled to 60°C and then poured into the water and stirred for 30 min. 1-(4-Nitrophenyl) piperidine (II ) collected by filtration and dried.
Yield: 6.0 g, 97%.
Purity: 98% by HPLC.

Example 2: Preparation of 1-(4-Nitrophenyl) piperidine (II).
A potassium carbonate (96.47g 0.6981 mol) was added to the solution of piperidine(59.44g 0.6981 mol) and 1-chloro-4 nitro benzene (0.6346 mol) in 500 mL in DMSO. The content was heated to 115-125 °C. After completion of reaction, the reaction mixture was cooled to 60°C and then poured into the water and stirred for 30 min. 1-(4-Nitrophenyl) piperidine (II ) collected by filtration and dried.
Yield: 126.98 g, 97%.
Purity: 98% by HPLC.

Example 2: Preparation of 1-(4-Nitrophenyl) piperidin-2-one (I).
Acetic acid (0.0049 mol) was added to the solution of 1-(4-nitrophenyl) piperidine (0.0097 mol) in 20 mL in acetonitrile at 25-30 °C. The content was heated to 45-50°C, the aq. sodium chlorite solution (0.049 mol) was dripped at 45-50°C and then maintained the reaction for 2-3 hrs. After completion of reaction, saturated solution of aq. sodium sulfite was added at 25-30°C and stirred for 30 min. Organic layer was separated, aq. Layer was extracted with acetonitrile. Organic layers were combined and distilled under vacuum to get residue. Thereafter, residue dissolved in toluene, washed with water, toluene distilled under vacuum to afford desired product as yellow solid.
Yield: 1.8 g, 85%.
Purity: 93%by HPLC.

Example 3: Preparation of 1-(4-Nitrophenyl) piperidin-2-one (I).
Acetic acid(0.0049 mol) was added to the solution of 1-(4-nitrophenyl) piperidine (0.0097 mol in 20 mL of acetoneat 25-30°C. The content was heated to 45-50°C, the aq. sodium chlorite solution (0.049 mol) was dripped at 45-50°C and then maintained the reaction for 2-3 hrs. After completion of reaction, saturated solution of aq. Sodium sulfite was added at 0-30°C and was stirred for 30 min. Organic layer was separated, aq. Layer was extracted with Ethyl acetate. Organic layers were combined and distilled under vacuum to get residue. Thereafter, residue dissolved in toluene, washed with water, toluene distilled under vacuum to afford desired product as yellow solid.
Yield: 1.95 g, 90%.
Purity: 94% by HPLC.

Example 4: Preparation of 1-(4-Nitrophenyl) piperidin-2-one (I).
To the solution of 1-(4-nitrophenyl) piperidine (100 gm, 0.4848 mol) in 1000 mL of Acetonitrile, acetic acid (14.5 g, 0.241 mol) was added at 25-30°C. Heated the content at 45-50 °C, dripped the aq. Sodium Chlorite solution (2.41 mol) at 45-50 °C and maintained the reaction for 2-3 hrs. After completion of reaction, added saturated solution of aq. Sodium sulfite at 25-30 °C and was stirred for 30 min. Organic layer was separated, aq. Layer was extracted with Acetonitrile. Combine both organic layers and distilled out solvent at below 50°C under vacuum to get a residue. Thereafter, Toluene was added to get clear organic solution which was washed with Water. Distilled out organic layer at below 50 °C under vacuum to afford desired product as yellow solid. Yield: 90.76 g, 85%; Purity: 97%.

Example 5: Preparation of 1-(4-Nitrophenyl) piperidin-2-one (I).
Sodium dihydrogen phosphate (0.029 mol) was added to the solution of 1-(4-nitrophenyl) piperidine (0.0097 mol) in 60 mL of Acetonitrile at 25-30°C. The content was heated to 45-50 °C, the aq. sodium chlorite solution (0.049 mol) was dripped at 45-50°C and then maintained the reaction for 2-3 hrs. After completion of reaction, saturated solution of aq. sodium sulfite was added at 25-30°C and stirred for 30 min. Organic layer was separated, aq. Layer was extracted with acetonitrile. Organic layers were combined and distilled under vacuum to get residue. Thereafter, residue dissolved in toluene, washed with water, toluene distilled under vacuum to afford desired product as yellow solid.
Yield: 1.5 g, 70%.
Purity: 90% by HPLC.

Example 6: Preparation of 1-(4-Nitrophenyl) piperidin-2-one (I).
1-(4-nitrophenyl) piperidine (50 gm, 0.2424 mol) was dissolved in 500 mL of Acetone, Acetic acid (7.25 g, 0.120 mol) was added at 25-30 °C. Heated the content at 45-50 °C, dripped the aq. Sodium Chlorite solution (1.20 mol) at 45-50 °C and maintained the reaction for 2-3 hrs. After completion of reaction, added saturated solution of aq. Sodium sulfite at 25-30°C and was stirred for 30 min. Organic layer was separated, aq. Layer was extracted with Ethyl acetate. Combine both organic layer and distilled out solvent at below 50 °C under vacuum to get a residue. Thereafter, Toluene was added to get clear organic solution which was washed with Water. Distilled out organic layer at below 50 °C under vacuum to obtain yellow solid. Yield: 48.05 g, 90%; Purity: 98%.
,CLAIMS:We claim:

1) A process for the preparation of 1-(4-Nitrophenyl) piperidin-2-one of formula (I)

comprising
i) dissolving 1-(4-nitrophenyl)piperidine of formula (II)

in solvent;
ii) oxidizing the compound 1-(4-nitrophenyl)piperidine of formula (II) of step (i) using sodium chlorite in presence of acid to obtain 1-(4-Nitrophenyl) piperidin-2-one.

2) The process as claimed in claim 1, wherein solvent is an aprotic solvent selected from acetone, acetonitrile, propionitrile, butyronitrile, dimethylformamide (DMF), dimelthylsulfoxide (DMSO), dimethylacetamide (DMAC), methanol, ethanol, and toluene.

3) The process as claimed in claim 1, wherein acid is selected from formic acid, acetic acid, hydrochloric acid, phosphoric acid, carbonic acid.

4) The process as claimed in claim 1, whereinthe compound of formula (II) and oxidizing agent is used in ratio of 1:1 to 1:10.

5) The process as claimed in claim 1, wherein the oxidizing agent and acid is used in ratio of 1:0.1 to 1:5.